Childhood maltreatment (i.e., physical, sexual or emotional abuse by parents, peers or siblings, physical and emotional neglect) has an enormous impact on risk for substance abuse and dependence. The Adverse Childhood Experience Study reported that exposure to maltreatment-related adversity accounted for 64% of the population attributable risk for substance abuse. Understanding this association may be crucial to our efforts to prevent, preempt or treat drug abuse. During the previous funding period we conducted a series of studies to better understand the association between childhood maltreatment and substance use. We found in cross-sectional studies that exposure to physical maltreatment was a more significant risk factor for high levels of drug and alcohol use than emotional maltreatment, and that physical maltreatment (but not emotional maltreatment) was associated with marked alterations in T2-relaxation time (an indirect measures of cerebral blood volume assessed by MRI) in major components of the ascending dopamine system. T2-relaxation time in two components (dorsolateral prefrontal and anterior cingulate cortex) correlated with degree of drug and alcohol use. Further we found a strong statistical relationship between the size of the first lobule (lingula) of the cerebellar vermis in physically maltreated subjects and degree of substance use. We also found that substance use by maltreated individuals spiked at 20-21 years of age. The key aims of the proposed study are to test in a prospective study whether T2-relaxation time in dorsolateral prefrontal and anterior cingulate cortex, and large lingula size can predict degree of drug and alcohol use by maltreated individuals. Moreover, we will test the hypothesis that type and timing of exposure to maltreatment matters, and that there are sensitive periods when exposure to specific types of maltreatment are most likely to effect the development of these brain regions and to increase risk for drug abuse. This information will shed new light on our understanding of the relationship between maltreatment and drug abuse by examining the phenomenon from a developmental neuroscience perspective. These studies may provide the critical insights necessary to design programs to protect children during their most vulnerable periods, and to develop preemptive strategies to aid exposed individuals before their vulnerability becomes manifest. PUBLIC HEALTH RELEVANCE: Childhood maltreatment is a leading risk factor for drug abuse. We will study the problem from a developmental neuroscience perspective, and test the hypothesis that maltreatment during sensitive periods affects the development of dopamine system and cerebellum, and that alterations in these regions can predict risk for high levels of drug use in a prospective longitudinal study.